The Bcl-2 (B cell lymphoma) family of proteins are genetically and functionally well characterized as being critical in effecting cellular apoptosis. Within this family are proteins that function either to protect cells against apoptotic signals or that induce apoptosis. A balance of interactions between the pro- and anti-apoptotic Bcl-2 family proteins determines whether the cell undergoes apoptosis or remains healthy. Bcl-2 is found to be over-expressed in many tumors including B-cell lymphomas, adenocarcinomas of the colon and prostate, gastric and naso-pharyngeal cancers. Bcl-2 has also been implicated in resistance of tumor cells to chemotoxic drugs or radiation. Over-expression of Bcl-2 in T cells causes their inappropriate resistance to apoptotic cues and subsequent likely auto-reactivity. Furthermore, expression levels of various members of the Bcl-2 family of proteins effects the onset and progression of these diseases. Therefore, Bcl-2 family of proteins represents important molecular targets for therapeutic intervention for many diseases.
Short peptide binding motifs, or domains (e.g. BH3 domains), in this family of proteins mediate many of the key interactions. These domains share structural features that can be exploited in identifying novel therapeutics that regulate these interactions. A key challenge for the drug industry is to discover small molecules or peptides that block domain-mediated protein-protein interactions, and do so in a subset specific manor. Thus, a need exists for an assay system that can efficiently identify compounds that that regulate (inhibit or enhance) BCL-2 mediated apoptosis.